Pharmaceutical science is undergoing changes in its perception of diagnostic criteria for categorization of disease and the value of medications that are engineered to simultaneously bind to and affect the function of more than one target. For a number of years, the pharmaceutical industry has diligently followed the paradigm of single target-based drug discovery, but the successes with this approach for generating novel medication have declined drastically, leading many to question this approach (Csermely et al., 2005; Sams-Dodd, 2005). More recently, there has been significant discussion that design of multi-target drugs (those in which a single molecule can effectively interact with more than one target in a disease-perturbed pathway) may be a more optimal approach to discovering new and more effective medications (Lu et al., 2012; Pang et al., 2012). In terms of categorization of various disease states it has become obvious that a number of diseases thought to be categorically different, may have etiologically similar pathways determining the pathology. This is particularly evident with neurodegenerative diseases where recent work indicates that cell-to-cell transmission of misfolded proteins may be the underlying cause of several, previously thought to be different, disease states (e.g., Parkinsonism, Alzheimer's disease, Huntington's Disease, etc.) (Guo and Lee, 2014).
In psychiatric disease areas such as schizophrenia and affective/cognitive disorders, similar neurotransmitter pathways consistently come to attention, as evidenced by the recent review on the glycine transporter (Harvey and Yee, 2013). In this review the authors also draw attention to the fact that the glycine receptor and transporter systems in the central nervous system (CNS) also are involved in alcohol dependence, pain and epilepsy. A more direct discussion of the similarities between alcohol dependence and chronic pain disorders can be found in a review authored by Egli, Koob and Edwards entitled “Alcohol Dependence as a Chronic Pain Disorder” (2012). The possible relationship between alcohol dependence and chronic pain syndromes is underscored by the current reports that drugs which have been used to treat chronic pain are now being found to be efficacious in preventing relapse in alcohol dependent subjects. A demonstration of this phenomenon is the use of gabapentin (which is a T-type calcium channel blocker) to treat chronic pain (Moore et al., 2014) and alcoholism (Mason et al., 2014).
Throughout the world millions of people suffer from chronic pain (e.g., 116 million in the U.S. alone (Institute of Medicine, 2011) and from alcohol abuse and dependence (e.g., 18 million in the U.S. (Grant et al., 2004)) or both, and similarities in the neurochemistry subsuming both chronic pain syndromes and alcohol dependence go well beyond the common involvement of T-type calcium channels. Three neurochemical systems have, in particular, been linked to both chronic pain and alcohol dependence. These systems are the GABA, cannabinoid and the opioid transmitter systems in brain and spinal cord (Zeilhofer et al., 2012). The GABA-A receptor system has been linked to both the acute and chronic actions of ethanol including the development of dependence and the generation of craving during periods of abstinence (Enoch et al., 2013; Kumar et al., 2004; Tabakoff and Hoffman, 2013). Chronic ethanol consumption by mice upregulates (increases expression of) delta opiate receptors in the CNS (van Rijn et al., 2012), and delta opiate receptor expression and function in certain areas of brain (e.g., ventral tegmental area) has been shown to modulate ethanol consumption by animals (Clapp et al., 2008). Some of the effects of agents which act as agonists at the delta opioid receptors have been proposed to be mediated via modulation of GABA neuron function (Kang-Park et al., 2007). The most informative recent description of how delta opiate receptors can modulate GABA-A receptor function is contained in (Margolis et al., 2011) and in that report, it is stressed that increases in delta receptor function “only appear following challenges such as inflammation, stress and administration of rewarding (addicting) drugs”, and that such increases in function can change activity of other neurotransmitter systems (e.g., GABA).
The upregulation of delta opiate receptors is also a definitive aspect of the development of chronic pain (Cahill et al., 2003) and mice with genetic deletion of the delta opiate receptor are inherently more sensitive to painful stimuli (Gaveriaux-Ruff et al., 2011). Although it is rational to consider that delta opiate receptors are good targets for pharmaceuticals to treat chronic pain, there are currently no delta opiate receptor selective drugs approved by the Food and Drug Administration and some candidates have failed in Phase II clinical trials (van Rijn et al., 2013). A confound in the simplistic view that delta opiate receptors in and of themselves can reduce chronic pain, is that tolerance rapidly develops to the antihyperalgesic actions of delta opiate receptor agonists. Part of this “tolerance” mechanism is mediated via increased inhibition of GABA release in spinal cord and brain stem by upregulated delta opiate receptors which arise during development of chronic pain (Taylor, 2009; Zhang et al., 2006).
There also has been discussion in the literature that one should consider the possibility of preventing the development of chronic pain by medications administered in the early phase of the neuropathological process that produces chronic (neuropathic) pain syndromes (Kehlet et al., 2006; Van de Ven and John Hsia, 2012). One of the more accepted mechanisms for the progression of acute injury to chronic pain is an upregulation of voltage sensitive sodium channels (e.g., Nav1.7 and Nav1.8) in sensory neurons (Belkouch et al., 2014; Strickland et al., 2008). Studies performed with endogenous delta receptor agonists such as enkephalin have indicated that activation of delta opiate receptors can prevent the upregulation of Nav1.7 in sensory neurons in rats treated to produce diabetic neuropathy (Chattopadhyay et al., 2008). Interestingly, the transfection of neurons with a vector, resulting in a constant release of GABA, also prevented the pathologic increase in Nav1.7 resulting from chronic hyperglycemia (diabetes) (Chattopadhyay et al., 2011). Additionally, there is evidence that delta opiate receptors present in Nav1.8-expressing nociceptive sensory neurons play a critical role in pain mechanisms (Gaveriaux-Ruff et al., 2011). Thus one can postulate that a novel medication that can activate both GABA receptors and delta opiate receptors may prevent the development of chronic (neuropathic) pain syndromes by interfering with the pathology induced upregulation of Nav1.7 and 1.8 channels and/or other mechanisms. A medication that can simultaneously activate GABA receptors (Zeilhofer et al., 2012) and activate delta opiate receptors, as well as inhibiting the Nav 1.7 and 1.8 channels, can also be of benefit in reducing pain even after the development of a chronic pain syndrome.
The cannabinoid neurotransmitter system of the brain and spinal cord, in many ways resembles the opioid transmitter system. The endogenous agonists for cannabinoid and opiate receptors differ (i.e., anandamide is the agonist at the cannabinoid (CB1) receptors, while enkephalins are the agonists at the delta opiate receptors), but the receptor characteristics and physiologic function of the cannabinoid (CB1) receptor and the delta opiate receptor are quite similar. Both are G protein coupled receptors (GPCRs) that signal through the Gi/Go proteins and affect the function of the same set of neuronal enzymes and channels which carry out the CB1 and delta opioid receptor effects (Howlett et al., 2002). Both CB1 receptors and delta opiate receptors have been designated as targets for control of chronic pain syndromes (Normandin et al., 2013; Pernia-Andrade et al., 2009), and for reducing craving and high levels of alcohol consumption in alcohol dependent animals (Femenia et al., 2010; van Rijn et al., 2010). It is notable that pharmacological and direct interactions between delta opiate receptors have also been noted (Manzanares et al., 1999; Vigano et al., 2005). Particularly in the control of pain, delta 9-tetrahydrocannabinol (THC, a CB1 receptor agonist) has been shown to have synergistic effects with opiates, and these effects of THC have been stated to result from its actions at the delta opiate receptor, as well as CB1 receptors (Cichewicz, 2004). A more current theory of CB1 receptor and delta opiate receptor interactions is that there is a physical interaction (heterodimerization) between these receptors (Rios et al., 2006). Therefore, medications that affect the function of the CB1 cannabinoid receptor or the delta opiate receptor can modulate the activity of the interacting partner receptor system and have similar end effects on GABA release (Olive, 2010).
A joint, beneficial effect of multi-modal medications may as well be seen in preventing and treating relapse in alcoholics. By simultaneously enhancing GABA-A receptor function during a period of alcohol withdrawal in an alcohol dependent animal and modulating of cannabinoid or delta opiate receptors in a dependent subject (Bie et al., 2009a), control of craving and a reduction of relapse can be achieved.
The recent revision (the fifth) of the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM V) defines alcoholism (Alcohol Use Disorder, AUD) by eleven criteria, of which two have to be met during the same 12 month period for an individual to be diagnosed as suffering from AUD (NIH Publication No. 13-7999, 2013). A novel addition to DSM V is a criterion of craving to the list of criteria that can define AUD. Craving was not a component of earlier DSM diagnostic criteria, but over recent years, the concept and phenomenon of craving has become a primary reason for individuals to relapse to alcohol use after a period of sobriety (Anton, 1999). Craving in the context of DSM V, is distinguished from attempts by an individual to control withdrawal signs which occur early (within a day or two) after an individual stops consuming ethanol, and alcohol or a closely related substance such as benzodiazepines may be taken to relieve withdrawal signs. The overt signs of alcohol withdrawal in humans last for five days to a week, and in terms of treatment, constitute the detoxification stage of treating alcoholism. The manifestations of craving as defined by DSM V and in other publications (Kavanagh et al., 2013) are cognitive-emotional events over a period of years rather than days, and are manifestations of limbic system function (Heinz et al., 2009). The early withdrawal signs are a neural hyperactivity syndrome exhibited over most of the brain with particular involvement of the cerebral cortex (Coutin-Churchman et al., 2006). One of the most significant distinctions between the biologic characteristics of the withdrawal syndrome and the later manifestations of craving is in terms of pharmacologic treatments. For instance, benzodiazepines are commonly used to advantage in treating the acute stages of the alcohol withdrawal syndrome, but are contraindicated for more prolonged use in allay craving (Licata and Rowlett, 2008). On the other hand, the drugs most currently used in the U.S.A. for treating craving and preventing relapse, i.e., acamprosate and naltrexone, are significantly more effective if given after detoxification or after a prescribed period (weeks) of abstinence.
There is an ongoing need for medications that can treat chronic pain, addiction, addiction relapse, and the like. Methods of synthesis of substituted quinolone ureas are disclosed herein, which significantly expands on the series of chemical entities which have substitutions on the terminal nitrogen of 4-ureido-5,7-dihalo-2-carboxy-quinolines and in which the 2-position is a carboxy group, an ester, a ketone, an ether or an amide. Certain of the compounds synthesized by the methods described herein unexpectedly have affinity for and pharmacological actions at the mammalian GABA-A receptor, the cannabinoid (CB1) receptor, the voltage sensitive sodium channels (Nav 1.7 and 1.8) and/or the delta opiate receptor while having little or no affinity for a large number of other receptors/channels/enzymes.
GABA-A receptors are agonist gated ion channels which respond to the presence of the neurotransmitter GABA by increasing permeability to chloride ions and thus generating hyperpolarization and inhibition of ongoing activity in neurons. The GABA-A receptors are composed of five distinct protein subunits with the majority of the GABA-A receptors in brain having a composition consisting of two alpha (α) subunits, two beta (β) subunits and one gamma (γ), delta (δ), theta (θ) or pi (π) subunit. Currently 19 GABA-A receptor subunits are known (α 1-6, β 1-3, γ 1-3, δ, ε, θ, π and 3 rho (ρ) subunits).
GABA-A receptors are the site of action of a number of clinically important drugs such as benzodiazepines, barbiturates, anesthetics, analeptics, neuroactive steroids, etc. and all of these drugs interact with binding sites that are partially or completely distinct from one another. These binding sites, including the binding sites for GABA itself, are generated by the interactions of various subunits and are formed at the interface of the various subunits that come together to produce the pentameric combination that characterizes the native GABA-A receptors in brain and spinal cord. Given the large number of subunit combinations that are possible (although not all have been demonstrated) it is not surprising that the GABA-A receptor demonstrates a complex pharmacologic profile.
A large number of molecules have been synthesized and shown to interact with GABA-A receptors of a particular subunit combination, and these molecules display a variety of pharmacologic characteristics including sedation, anesthesia, anxiolysis, anticonvulsant effects, muscle relaxation, analgesia, antipsychotic actions and even modulation of immune system function depending on the subunits present in particular GABA-A receptors and the way in which the subunits interact.
The most common type of GABA-A receptor present in brain consists of two α1 subunits, two β2 subunits and a γ2 subunit and these receptors are mostly located within the membrane of the post-synaptic neuron at the synapse. These and other synaptically located GABA-A receptors are mediators of phasic GABA signals in response to GABA release from the pre-synaptic terminal. On the other hand, GABA-A receptors that contain a δ subunit instead of a γ subunit are located extra-synaptically (outside of the synapse) and generate a tonic inhibition of the post-synaptic neuron in response to GABA that “leaks” out of the synaptic cleft. These extra-synaptic GABA-A receptors, not only are distinguished by their δ subunit but also by α subunits. The extra-synaptic GABA-A receptors can contain only α1, α4 or α6 subunits in association with the δ subunit.
The α1 subunit in association with the δ subunit is primarily found in the interneurons and pyramidal cells of the hippocampus, the α4 together with δ is expressed in the thalamic relay neurons and dentate gyrus granule cells and the α6 and δ subunit containing GABA-A receptors are primarily localized to the cerebellar granule cells. The different anatomical distribution of particular α subunits in conjunction with the δ subunit bespeaks different function and further physiologic differences exist between the different α and δ subunit combinations. For instance, the extra-synaptic GABA-A receptors composed of the α1 β2 or β3, and δ subunits have very low permeability for chloride ions even in the presence of high concentrations of GABA. On the other hand, these “silent” receptors are quite active when GABA is applied together with a positive allosteric modulator which is effective at δ subunit containing GABA-A receptors. It is therefore clear that discovery of molecular entities that have selectivity for particular subunit combinations within the GABA-A receptor can generate novel medications either with predicted or unanticipated spectra of physiologic or anti-pathologic effects.
Given the above described literature on the involvement of GABA-A, CB1 and delta opiate receptors in relapse drinking in alcohol dependent subjects and in the etiology of chronic pain syndromes, a series of the compounds described herein were tested in animal models of relapse drinking and chronic pain syndromes. A pattern of effects was observed that can predict that particular N-substituted-4-ureido-5,7-dichloro-2-carboxy (or carboxyester)-quinolines can be effective in preventing relapse in addicted humans and also can be effective in treatment and prevention of chronic neuropathic pain in humans.